Blocking P2X7 receptor ameliorates oxidized LDL-mediated podocyte apoptosis

Zhu, Yanji; Li, Qian; Xun, Wenlong; Chen, Yuan; Zhang, Caihui; Sun, Song

doi:10.1007/s11033-019-04823-6

Cited by 6 publications

(2 citation statements)

References 26 publications

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“…Interestingly, the P2X7R antagonist (A438079) decreased the EGCs death, as demonstrated here by reduced PS and annexin V binding and caspase 3/7 activity, showing the potential role of this receptor in promotes EGCs death induced by C. difficile toxins. The involvement of P2X7R in cell death has also been shown in other cells such as podocytes (70), macrophages (71), cerebellar astrocytes (72) and in neurons (73,74). Mitogen-activated protein kinase (MAPKs) such as extracellular signal-regulated kinase (ERK) 1/2 and JNK have also been associated with cell death mediated by this receptor.…”

Section: Discussionmentioning

confidence: 88%

Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia

et al. 2022

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Clostridioides difficile (C. difficile) produces toxins A (TcdA) and B (TcdB), both associated with intestinal damage and diarrhea. Pannexin-1 (Panx1) channels allows the passage of messenger molecules, such as adenosine triphosphate (ATP), which in turn activate the P2X7 receptors (P2X7R) that regulate inflammation and cell death in inflammatory bowel diseases. The aim of this study was to verify the effect of C. difficile infection (CDI) in the expression of Panx1 and P2X7R in intestinal tissues of mice, as well as their role in cell death and IL-6 expression induced by TcdA and TcdB in enteric glial cells (EGCs). Male C57BL/6 mice (8 weeks of age) were infected with C. difficile VPI10463, and the control group received only vehicle per gavage. After three days post-infection (p.i.), cecum and colon samples were collected to evaluate the expression of Panx1 by immunohistochemistry. In vitro, EGCs (PK060399egfr) were challenged with TcdA or TcdB, in the presence or absence of the Panx1 inhibitor (10Panx trifluoroacetate) or P2X7R antagonist (A438079), and Panx1 and P2X7R expression, caspase-3/7 activity and phosphatidylserine binding to annexin-V, as well as IL-6 expression were assessed. CDI increased the levels of Panx1 in cecum and colon of mice compared to the control group. Panx1 inhibitor decreased caspase-3/7 activity and phosphatidylserine-annexin-V binding, but not IL-6 gene expression in TcdA and TcdB-challenged EGCs. P2X7 receptor antagonist accentually reduced caspase-3/7 activity, phosphatidylserine-annexin-V binding, and IL-6 gene expression in TcdA and TcdB-challenged EGCs. In conclusion, Panx1 is increased during CDI and plays an important role in the effects of C. difficile toxins in EGCs, participating in cell death induced by both toxins by promoting caspase-3/7 activation via P2X7R, which is also involved in IL-6 expression induced by both toxins.

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Section: Discussionmentioning

confidence: 88%

Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia

et al. 2022

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“…This augmentation correlates with IL-8 secretion and p38 phosphorylation [ 62 ]. Metabolic cues, elevated glucose levels [ 78–81 ] and oxidized low-density lipoprotein (oxLDL) [ 60 , 82 ], further contribute to the upregulation of P2X7R expression. This is thought to exacerbate P2X7 mediated inflammatory responses and endothelial dysfunction.…”

Section: P2x7 Pharmacologymentioning

confidence: 99%

Ionotropic purinergic receptor 7 (P2X7) channel structure and pharmacology provides insight regarding non-nucleotide agonism

Al-Aqtash,

Collier

2024

Channels

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P2X7 is a member of the Ionotropic Purinergic Receptor (P2X) family. The P2X family of receptors is composed of seven (P2X1–7), ligand-gated, nonselective cation channels. Changes in P2X expression have been reported in multiple disease models. P2Xs have large complex extracellular domains that function as receptors for a variety of ligands, including endogenous and synthetic agonists and antagonists. ATP is the canonical agonist. ATP affinity ranges from nanomolar to micromolar for most P2XRs, but P2X7 has uniquely poor ATP affinity. In many physiological settings, it may be difficult to achieve the millimolar extracellular ATP concentrations needed for P2X7 channel activation; however, channel function is implicated in pain sensation, immune cell function, cardiovascular disease, cancer, and osteoporosis. Multiple high-resolution P2X7 structures have been solved in apo-, ATP-, and antagonist-bound states. P2X7 structural data reveal distinct allosteric and orthosteric antagonist-binding sites. Both allosteric and orthosteric P2X7 antagonists are well documented to inhibit ATP-evoked channel current. However, a growing body of evidence supports P2X7 activation by non-nucleotide agonists, including extracellular histone proteins and human cathelicidin-derived peptides (LL-37). Interestingly, P2X7 non-nucleotide agonism is not inhibited by allosteric antagonists, but is inhibited by orthosteric antagonists. Herein, we review P2X7 function with a focus on the efficacy of available pharmacology on P2X7 channel current activation by non-nucleotide agonists in effort to understand agonist/antagonist efficacy, and consider the impact of these data on the current understanding of P2X7 in physiology and disease given these limitations of P2X7-selective antagonists and incomplete knockout mouse models.

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P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy

Qian

Che

et al. 2023

Free Radical Biology and Medicine

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Blocking P2X7 receptor ameliorates oxidized LDL-mediated podocyte apoptosis

Cited by 6 publications

References 26 publications

Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia

Role of Pannexin-1-P2X7R signaling on cell death and pro-inflammatory mediator expression induced by Clostridioides difficile toxins in enteric glia

Ionotropic purinergic receptor 7 (P2X7) channel structure and pharmacology provides insight regarding non-nucleotide agonism

P2X7R/AKT/mTOR signaling mediates high glucose-induced decrease in podocyte autophagy

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